A Metabolic Trap for ME/CFS?

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Robert Phair provided a short update on ResearchGate about when he thinks he will present at the Symposium.
There will be a public CFS Community Symposium at Stanford on Saturday, September 29. There are many speakers with more experience in CFS research than me.

Nevertheless, I have been invited to speak.

So, if you want to hear the latest on metabolic traps in ME/CFS you can sign up for the livestreamed all- day conference using this link:
https://livestream.com/accounts/1973198/ME-CFS-2018

I believe my talk will be at approximately 4:00 PM (16:00) (USA Pacific Time), on September 29.
This Symposium is sponsored by the Open Medicine Foundation.
LINK
 
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wigglethemouse

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Robert Phair provided this update on ResearchGate on Oct 21 2018
PhairIDOmetabolictrapmodel.png
The IDO metabolic trap model

This is a diagram of the mathematical model used to produce the simulations I presented in my lecture at the 2018 OMF CFS Community Symposium at Stanford. Black arrows represent chemical reactions or transport. Colored rectangles represent molecules either inside or outside the cell. Red dotted lines terminated by a minus represent inhibition. Green dashed lines terminated by plus represent activation or catalysis.

In my view (as of October 2018), there are many unlikely combinations of events that can drive a person into this trap. But eliminating these initial causes will not result in escape from the trap. In other words, the way out is not the reverse of the way in. In this respect the metabolic trap hypothesis is similar to the Naviaux hypothesis for CFS.

The IDO metabolic trap is NOT conclusively established. We're working hard to convince ourselves that it's a real feature of ME/CFS and, if so, to find a way out of the trap. My work is funded by the Open Medicine Foundation.
Link : https://www.researchgate.net/projec...igue-Syndrome/update/5bccc73c3843b006753f99c2
 
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wigglethemouse

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and this update on Nov 8 2018
Metabolic trap talk now up on OMF's YouTube channel
Here's a link to my full talk on the IDO Metabolic Trap Hypothesis at the 2018 Stanford/OMF Community Symposium.

https://www.youtube.com/watch?v=uej1LXzRbnY&index=17&list=PLl4AfLZNZEQPxjqF4ojAO3wdCFMeriNBK&t=0s

As Ron Davis says, following my talk, this hypothesis is NOT established fact. "That's what science is", he said, "constant disappointment." Then the audience laughs.

But every scientist knows exactly what Ron means. Science is hard work.

Just as important, though, is that those disappointments tell us how to proceed. Every experiment that proves a theory wrong gets us closer to the truth. I think we're running on a good track. Please stay tuned.
Link : https://www.researchgate.net/projec...igue-Syndrome/update/5be3d6c7cfe4a76455009010
 

Belbyr

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I was curious, how does this line up with Dr Klimas's group in Florida. I know they are trying to alter gene function as well...

This is all really encouraging stuff. I like to see the excitement in Dr. Ron Davis's face when he did his closing statements. I anticipate seeing Whitney being back to health in the next year to 2 years, as long as government red tape doesn't hold things up.
 

Research 1st

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I was curious, how does this line up with Dr Klimas's group in Florida. I know they are trying to alter gene function as well...

This is all really encouraging stuff. I like to see the excitement in Dr. Ron Davis's face when he did his closing statements. I anticipate seeing Whitney being back to health in the next year to 2 years, as long as government red tape doesn't hold things up.
Think again my friend. Red tape? In the givsrnments eyes, there is no tape and no finish line. What do you think the useless time wasters have been doing to us with the B.S about mind-body for the last 30+ years?

The positive news? There are on going privately funded projects that will take 5 years from now to complete. The bad news? These are just the first main steps to complete which will bring some definate answers for CFS evidence based treatment. Many other studies then need to be designed, funding applied for, then completed. This takes at least 10 more years, just ask Dr Klimas how long large scale thorough studies to comprehensively prove a cause of CFS will take. She'll agree with me.

Reality is, it will take around 20 years from now just with tens of millions in private donations. Sorry to break it to you, but CFS is a medico political illness like no other. The NIH have done nothing for 20 years and never will. They ignore Ron. Think why. They can't discover what they helped spread by neglect.

The government will never fund proving an organic cause of CFS (to the level desperately required) because the people who allowed CFS to spread, are still alive. This includes the criminal liars who created the world wide ruse of CBT/GET who are already promoted and will only climb in power and stature politically to make them untouchable in court.

Science will only accept multi centre, multi country, peer reviewed papers on the cause of CFS (to demonstrate a functional cure) involving studies of 500+ patients at a time.

OMF finding the answer of what organic CFS is, will simply be held back politically as they know millions of educated wealthy victims want revenge, which means jailing the people who trapped maybe 17-100 million people around the world in a lie of CFS = mental illness. (NB: Majority of CFS aren't diagnosed or misdiagnosed as you need to be physically significantly disabled to be diagnosed due to no test available). This hides the true scale of the horror of what the CDC and others have done.

It's thus far more cost effective, politically, for each successive administration to let the CFS victims die out. They've done this since around 1969 -1988 depending if you believe ME is CFS. Either way, nothing will or can stop this. Only the rich will survive as they will bypass politics. The rest of us will all perish, well, those over 50.

You are aware elite CFS patients are already so much better since Mikovits was "wrong"? The patients with money take supplements that cost upwards of $1000 a month, anti virals, antiretrovirals, oxygen chambers, have multiple doctors their own nurses at home and all of this is out of our hands without a cheap, cost effective treatment.

All the government will do is sit on their hands with OMF breakthroughs just like they've done with Lyme and Autism. Think why they have the audacity to treat fellow humans like cattle. Why? Because they can, and humans unless well controlled, are ostensibly prone to evil when handed ultimate power. All the greatest psychology studies have taught us this.

What keeps us needlessly sick isn't just lack of Science but power. The power to deny us government access to appropriate levels of biomedical research funding and this happens for reasons none of us will ever be told about and will only surface in 100 years plus just like all the other scandals we hear about that happened at the time of our great grandparents.

The people who destroyed our lives cannot be defeated. They will retire with a flawless pedigree career, immune from prosecution and that will be that.

I wish I was wrong bit I'd bet anyone here a lot of apologies we'll all be sitting here in 10 years, watching Youtube conference updates, empty handed more sick as we age.

I love the OMF but they will be held hostage politically by the criminal elements in charge by blocking critical large scale funding.
 
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I was curious, how does this line up with Dr Klimas's group in Florida. I know they are trying to alter gene function as well....
It seems to line up conceptually, but they are taking different approaches, and not working together directly. OMF is not funding Klimas’s work. She does not have a funding stream right now for all the clinical trials that she wants to run, which seems a pity. (edited for accuracy)

This is an interesting presentation by Broderick on Klimas’s team. It gets good around 25 mins in.

https://www.nova.edu/promo-k.html?id=lecture4&video=1_ey09b79t&title=The Institute for Neuro Immune Medicine&subtitle=Modelling Exercise Dynamics to Restore Immune Signaling in ME/CFS&preview=http://www.nova.edu/nim/images/lecture-vid04.jpg
 
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Belbyr

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Both are valid points. My thinking is the computer learning along with the use of drugs that are already on the market are going to cut down on time, significantly! Also factor in the drive to get it done by the researchers because of their families. I don't see these people as just trying to get paid to publish a few papers or journal entries as Ron Davis said...

Maybe 2 years is optimistic, but perhaps there will be something that at least helps in that time frame.
 

HowToEscape?

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@Research 1st

I agree with the main thrust of your post, and your anger is both justified and necessary. Without it, the essential enabler will remain in place.
But I must disagree with your point about autism: I know of number of people who work with or have a degree of autism, and there is considerable amount of government funding for early intervention. That is the best treatment for autism, and much better than trying to monkey around with complex issues of the brain snd body. Nobody understands exactly what autism is, much less how it works, and so trying to medically “fix” an autistic kid is roughly a dart throwing exercise.

Some parents of autistic kids resort to bizzarre diets and interventions (Such as feeding the kids concentrated bleach), which are typicially more for the parents entertainment than the benefit of the child. So in that case, more or less the correct approach is actually being taken by the government, which is well above the normal performance.
Eventually, bureaucracies will make treatment more rigid and less effective, chasing out the most competent and replacing them with the most certificated, but at the moment there are fairly dedicated people working in the field.
 
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Wayne

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Some parents of autistic kids resort to bizzarre diets and interventions (Such as feeding the kids concentrated bleach), which are typicially more for the parents entertainment than the benefit of the child.
Sorry, but I have to vociferously disagree with these comments. The "concentrated bleach" you're referring to I assume is the chlorine dioxide solution that has been used by some to try to treat autisim. Chlorine dioxide is not concentrated bleach. And the amount that's used is quite miniscule. And there ARE a good number of examples where it did improve autism dramatically.

I'm aware of a large number of autisitic children improving significantly by changing their diet, and/or doing any number of other things like HBOT. Those parents doing this for their children are NOT doing it for "entertainment" (why you would even say that is beyond me). They're doing it because they've usually done a lot of research, and are diligently trying to do the very best by their children. Why someone would think otherwise is perplexing to me to say the least.
 
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Neunistiva

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OMF is not funding Klimas’s work. She does not have a funding stream right now for the clinical trials that she wants to run, which seems a pity.
What about this:

At least one major disease group thinks Dr. Klimas has struck gold with her approach. The Parkinson’s Foundation is apparently so excited at the possibilities of computational biology that they wanted to transport her and her entire team into Parkinson’s research. When that thankfully failed, they gave her a nice, big budget to get access to the computational modeling platform and train another team how to use it.

In return, she asked the Parkinson’s Foundation to fund a 20-person ME/CFS trial. That trial is expected to begin this fall. It will include post-menopausal women and use the same drug combination (etanercept and mifepristone) used in the GWI trial.
 
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Yes.. sorry, brain fog.. I should have been more specific. She doesn’t have all of them funded.. so pre-menopausal women are not funded, men are half funded. She gave a talk recently about the trials and said there is no funding mechanism w NIH for clinical trials, and I believe Solve does not fund trials? But yes, she does have the one you mentioned above funded, and half of a trial for men is too.

Here is her talk... https://sharkmedia.nova.edu/media/M...tCQoOQFeTVuiL_nT7A7XAwcs76qanLKf25UpB0sKUTJ7A
 

Hopeful1976

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Think again my friend. Red tape? In the givsrnments eyes, there is no tape and no finish line. What do you think the useless time wasters have been doing to us with the B.S about mind-body for the last 30+ years?

The positive news? There are on going privately funded projects that will take 5 years from now to complete. The bad news? These are just the first main steps to complete which will bring some definate answers for CFS evidence based treatment. Many other studies then need to be designed, funding applied for, then completed. This takes at least 10 more years, just ask Dr Klimas how long large scale thorough studies to comprehensively prove a cause of CFS will take. She'll agree with me.

Reality is, it will take around 20 years from now just with tens of millions in private donations. Sorry to break it to you, but CFS is a medico political illness like no other. The NIH have done nothing for 20 years and never will. They ignore Ron. Think why. They can't discover what they helped spread by neglect.

The government will never fund proving an organic cause of CFS (to the level desperately required) because the people who allowed CFS to spread, are still alive. This includes the criminal liars who created the world wide ruse of CBT/GET who are already promoted and will only climb in power and stature politically to make them untouchable in court.

Science will only accept multi centre, multi country, peer reviewed papers on the cause of CFS (to demonstrate a functional cure) involving studies of 500+ patients at a time.

OMF finding the answer of what organic CFS is, will simply be held back politically as they know millions of educated wealthy victims want revenge, which means jailing the people who trapped maybe 17-100 million people around the world in a lie of CFS = mental illness. (NB: Majority of CFS aren't diagnosed or misdiagnosed as you need to be physically significantly disabled to be diagnosed due to no test available). This hides the true scale of the horror of what the CDC and others have done.

It's thus far more cost effective, politically, for each successive administration to let the CFS victims die out. They've done this since around 1969 -1988 depending if you believe ME is CFS. Either way, nothing will or can stop this. Only the rich will survive as they will bypass politics. The rest of us will all perish, well, those over 50.

You are aware elite CFS patients are already so much better since Mikovits was "wrong"? The patients with money take supplements that cost upwards of $1000 a month, anti virals, antiretrovirals, oxygen chambers, have multiple doctors their own nurses at home and all of this is out of our hands without a cheap, cost effective treatment.

All the government will do is sit on their hands with OMF breakthroughs just like they've done with Lyme and Autism. Think why they have the audacity to treat fellow humans like cattle. Why? Because they can, and humans unless well controlled, are ostensibly prone to evil when handed ultimate power. All the greatest psychology studies have taught us this.

What keeps us needlessly sick isn't just lack of Science but power. The power to deny us government access to appropriate levels of biomedical research funding and this happens for reasons none of us will ever be told about and will only surface in 100 years plus just like all the other scandals we hear about that happened at the time of our great grandparents.

The people who destroyed our lives cannot be defeated. They will retire with a flawless pedigree career, immune from prosecution and that will be that.

I wish I was wrong bit I'd bet anyone here a lot of apologies we'll all be sitting here in 10 years, watching Youtube conference updates, empty handed more sick as we age.

I love the OMF but they will be held hostage politically by the criminal elements in charge by blocking critical large scale funding.
So hopeless then for us huh. Nice to read. Thanks for that
 

JES

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Reality is, it will take around 20 years from now unless a billionaire funds the OMF with tens of millions in donations. Sorry to break it to you, but CFS is a medico political illness like no other.
I don't think Ron Davis has any plans to continue ME/CFS research if or when he reaches the age of 100, so obviously they have a bit more short-term targets than 20 years. Why would it take 20 years to complete trials for already existing and approved drugs like Copaxone and Suramin? From my understanding OMF plans to begin testing these drugs shortly, i.e. in less than a year, and alongside that there is the metabolic trap hypothesis that might not need a drug treatment as such. Pessimistically we are talking about five years IMO. And regarding proving the cause definitively, that may take longer indeed but it's not necessary in order to have a treatment. We are still non the wiser to what is the cause of depression, Alzheimer's or Parkinson's disease, but there are still drugs available for these diseases.
 
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That is terrific to have Phair himself online answering questions. Credit to @Simon for writing a list of questions good enough to entice him.

I'm excited by some parts of Phair's ideas, including the bistability idea, and especially by the experimental hypothesis testing at the end. But I have two problems with it:

1. Starting with outbreaks.

His logic in looking for common genetic mutations is that there are outbreaks. But by far the majority of us got sick by ourselves. You could take any feature of the disease as your starting point: PEM, female prominence, comorbidity with POTS, etc, etc , and you choose one of the rarest features? I fear this sets the whole expedition off in the wrong direction.

2. The odds the genetic mutations he found were just chance.

The following is text from Phair in which he admits making 86 comparisons and still doubts it might be appropriate to use a Bonferroni correction. He also seems to ignore the base-rate of mutations in the various genes. In the key IDO2 gene the 20 severely ill patients had a 55% mutation rate. But the rate among healthy controls was 44%. That is just not a strong finding. I don't consider that sufficiently solid a foundation to build from.

When I first encountered the 5 mutations in IDO2, I was looking at genes one by one, manually. I started with all the mitochondrial proteins in the electron transport chain, then moved on to central energy metabolism. IDO2 was the 86th gene I looked at in the SIPS study. So absolutely, to avoid false positives, you could say I should do a Bonferroni correction and insist on p < 0.05/86. But consider this. None of the previous 85 genes had even a single damaging mutation that was common to even 3 of the SIPS patients. In IDO2, I found two pretty common predicted damaging mutations and 3 rare damaging mutations and every SIPS patient had at least one. Moreover, even SIPS patients who did not have the most common damaging mutation had at least one and sometimes three other damaging mutations in the same gene. These did not seem like clues to ignore, no matter what Bonferroni says.

And when I realized that IDO1 was substrate inhibited, the idea of the metabolic trap lept out at me. It was exactly the kind of thing I was hunting for - a bistable system.

So, for me, statistics is the last resort. This process of looking for common damaging mutations began with a conviction based on the existence of ME/CFS epidemics. It's just logic. But I'm a classic Popperian hypothesis tester. Now that the hypothesis is formulated it makes predictions I can test. Testing hypotheses. This is where science gets done. It's also the hardest part. Nature does not make it easy to test hypotheses well.


I'm disappointed by this answer.

I hope I'm wrong about all this and Phair is on the right track..

 

alex3619

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The thing about stats is they tell you nothing about the absolute truth of an hypothesis. p values are a way of estimating the confidence we should have in an hypothesis. Either they are right, or they are wrong, but the p value does not tell you that. Its an expression of likelihood.

Now I would not accept the tryp-trap as a done deal, but neither does anyone at OMF. This requires more research. It requires the new assays. Creation of cell lines for testing would be fantastic. Determining exact IDO2 cell expression would be great. Further testing is needed on the Trp/Kyn ratios. Further testing is needed, and for this cell lines might be required, to determine if serotonin is a problem in the brain. All these things are on the way.

Let me give just a flavour of why I am less than keen on trusting stats in early research. Suppose they did a new study, but this time predicting only the tryp-trap response. Suppose its another twenty patients, just to avoid complications. Suppose they get the same results. Same number of patients, same data, but only one investigation so no correction. How would this be different from the first study? What changes is our CONFIDENCE, and this still wont prove the concept.

As I have already said, just based on metaknowledge about scientific hypotheses, we can predict there is a high risk of failure of the hypothesis. I would not want to stop testing because of that though ... we need strong data, not a metaknowledge heuristic.

This was also basically an initial investigation. Much more data is needed.

However as hypotheses go this one has the potential to explain more than any other I have ever seen. THAT is encouraging, though not proof. Many a fantastic hypothesis has failed in the history of science.